Staphylococcal enterotoxin B (SEB) is a polypeptide exotoxin produced by Staphylococcus aureus and belongs to a family of microbial proteins called "superantigens". SEB, directly binds to MHC class II molecules and potently activates both CD4+ and CD8+ T cells expressing certain T cell receptor (TCR) beta chain variable region irrespective of their antigen specificities. As a result, SEB can cause a variety of clinical illnesses ranging from self-limiting food poisoning to the more severe toxic shock syndrome, which can be lethal. By virtue of its robust immunostimulatory property, SEB can also be used as agents of bioterrorism or biological warfare. There is, however, a significant knowledge gap in our understanding of the immunopathogenesis of SEB, largely attributed to a dearth of suitable animal models. Poor binding of SEB to non-human MHC class II molecules results in ineffective activation of the immune system in common laboratory animals and restricts their use in SEB research. Nonetheless, transgenic expression of HLA class molecules in mice restores these defects and dramatically augments the immune response to SEB delivered by several different routes. Faithful reproduction of human diseases and amenability to a variety of immunological and genetic experimentations render HLA class II transgenic mice an ideal tool for studying the in vivo biological effects of Staphylococcal enterotoxin B. Using this robust model, we propose to thoroughly understand SEB-induced clinical syndrome and idetify effective theraeutic as well as preventive interventions for SEB-induced clinical syndrome. Specific Aim 1: Delineate the immunopathogenesis of the clinical syndrome resulting from airway exposure to SEB;Specific Aim 2: Identify effective immunomodulatory agents for the treatment of SEB-induced clinical syndrome; and Specific Aim 3: Design and evaluate novel vaccines specific for SEB. The bacterial toxin, Staphylococcal enterotoxin B (SEB), causes many human diseases and can also be used as a biological weapon. The mechanisms by which SEB causes diseases are poorly understood because there are no good laboratory animal models. We propose to use the unique line of mice developed by us (that express human molecules) to understand how SEB causes diseases and subsequently develop effective drugs/vaccines for treating and preventing diseases caused by SEB.